The analgesic effect of morphine decreases with repeated application. The underlying mechanism for this process, called tolerance, is not known. In recent years our understanding of the neural pathways that can be involved in this process has increased considerably. There is evidence indicating that morphine produces its analgesic effect at least in part by activating cells in the mesencephalic periaqueductal gray (PAG) which in turn excite cells in the caudal medulla including the nucleus raphe magnus (NRM). This results in an inhibition of those cells in the spinal cord which normally respond to pain. It has been shown in our laboratory that injection of glutamate into the PAG causes analgesia which is apparently mediated by activation of this neural pathway. Furthermore, there is evidence that cross tolerance can be produced between morphine and analgesia produced by glutamate. The purpose of this research is (1) to identify the neurotransmitters that can alter the activity of those cells in the NRM that respond to injection of glutamate into the PAG and (2) to determine what changes, if any, occur in this pathway during the development of morphine tolerance. The methods used will include microinjection into the PAG, recording from single cells in the PAG and in the NRM and microiontophoresis of drugs into the PAG and the NRM. These experiments will provide further insight into the mechanism of the analgesic action of morphine and to the tolerance to such effect.